RESUMO
BACKGROUND AND AIM: Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. METHODS: The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1 in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. RESULTS: TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migration in vitro as well as facilitated GC tumor growth and metastasis in vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. CONCLUSIONS: Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.
Assuntos
Proliferação de Células/genética , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Lipocalinas/genética , Lipocalinas/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Metástase Neoplásica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima/genética , Regulação para Cima/fisiologia , Animais , Linhagem Celular , Movimento Celular/genética , Modelos Animais de Doenças , Progressão da Doença , Proteínas da Matriz Extracelular/fisiologia , Feminino , Humanos , Lipocalinas/fisiologia , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: Genome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. METHODS AND RESULTS: The association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan-Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. CONCLUSION: rs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.
Assuntos
Povo Asiático , Fibrilação Atrial/etiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter , Idoso , Fibrilação Atrial/etnologia , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Análise de SobrevidaRESUMO
BACKGROUND: Atrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene. METHODS: A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study. RESULTS: In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF. CONCLUSIONS: Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.
Assuntos
Povo Asiático/genética , Fibrilação Atrial/genética , Predisposição Genética para Doença , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Idoso , Alelos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The H7N9 strain of bird flu is a new type of avian flu that was identified at the end of March 2013. The disease is concerning because most patients have become severely ill. PURPOSE: To study the X-ray and computed tomography (CT) findings of early H7N9 avian influenza cases. MATERIAL AND METHODS: Chest radiography and CT were performed in six patients with H7N9 avian influenza within 1-20 days after onset. The CT examinations included conventional spiral CT and high-resolution CT. The findings on the radiography and CT images were analyzed. RESULTS: Abnormal X-ray and CT findings were present in all of the patients. All of the cases had acute onset. In the early stage, the right lung was more commonly affected (particularly in the right upper and middle lobes). The lesions rapidly expanded to the entire lungs and were characterized primarily by ground-glass opacities (GGOs) combined with consolidation. Diffuse GGO was observed in all six cases (1 was symmetric, and 5 were non-symmetric). Local consolidation was found in four cases, and lobar consolidation was found in two cases. Normal lung tissue was observed between the lesions. Pleural thickening was common and was combined with pleural/pericardial effusion or mediastinal lymph node enlargement. Reticular changes, centrilobular nodules, and the tree-in-bud sign were observed in some cases, but reticular changes, bronchial wall thickening, and hyperinflation were not found. CONCLUSION: Radiological changes associated with both acute pneumonia and acute interstitial inflammation were observed in early H7N9 avian influenza cases. Serial chest X-rays were useful for the diagnosis and severity assessment of the disease. CT may provide a more accurate assessment of the lung pathology.
Assuntos
Subtipo H7N9 do Vírus da Influenza A , Influenza Humana/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Espiral/métodosRESUMO
Many clinical studies indicate that atrial fibrillation is closely related to hypertension. Atrial fibrillation is not only associated with the level of blood pressure (BP) but also with the circadian rhythms of BP. However, the underlying mechanisms of atrial fibrillation in essential hypertension patients remain largely unknown. Hypertension may facilitate the onset and persistence of atrial fibrillation by stretch-induced changes in the repolarization of atrial myocytes (triggers of atrial fibrillation) and atrial remodeling (structural and electrical remodeling). Importantly, the effects of hypertension on atrial fibrillation are progressive. These progressive anatomic, functional, electrophysiological and structural changes occur at different times. This characterization of the time course of atrial changes presents an intervention window before remodeling progresses to changes that are difficult to reverse. Given that the medium to long-term efficacy of antiarrhythmic drugs has proved poor, it is essential to seek new therapies to prevent the onset of atrial fibrillation and to effectively control recurrences of atrial fibrillation. The study of nonantiarrhythmic drugs that act on the atrial remodeling that constitutes the substrate of the arrhythmia is a new and very interesting field of research. Treatment with angiotensin-converting enzyme inhibitors angiotension-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) seems more promising. However, from recent trials, only hypertension with structural heart disease, left ventricular dysfunction and left ventricular hypertrophy benefit from ACEIs and ARBs. This article reviews many aspects of atrial fibrillatio in essential hypertension patients to provide the foundation of atrial fibrillatio treatment.
Assuntos
Fibrilação Atrial/etiologia , Hipertensão/complicações , Antiarrítmicos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Pressão Sanguínea , Frequência Cardíaca , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Fatores de Risco , Resultado do TratamentoRESUMO
Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD(90)) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD(90) variability. LPA increased L-type calcium current (I(Ca,L)) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (I(to)) and the delayed rectifier potassium current (I(K)). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S(1)S(2) stimulation. Notably, the effects of LPA on action potentials and I(Ca,L) are PTX-sensitive, suggesting LPA action requires a G(i)-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing I(Ca,L) in a G(i) protein-dependent manner.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Lisofosfolipídeos/fisiologia , Animais , Canais de Cálcio Tipo L/fisiologia , Sinalização do Cálcio , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Técnicas In Vitro , Lisofosfolipídeos/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Toxina Pertussis/farmacologia , Coelhos , Função Ventricular/efeitos dos fármacosRESUMO
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, but its pathogenesis is incompletely understood. Current evidences have highlighted the progression of atrial fibrosis and electrophysiological remodeling in AF development. Lysophosphatidic acid (LPA), the simplest phospholipid, is associated with fibrotic disease and promotes proliferation of a wide variety of fibroblast. It was demonstrated that LPA stimulation in many cell types such as human endothelial cells, human renal fibroblasts, and myoblasts, significantly upregulates connective tissue growth factor (CTGF) expression, which acts as a downstream signaling effector for transforming growth factor-ß1 (TGF-ß1) to drive fibrosis. We hypothesized that LPA could also evoke growth factor-like responses to atrial fibroblast, and subsequently induce atrial fibrosis to trigger AF. LPA is also verified to involve in numerous electrophysiological activities in non-myocardiocytes. So LPA is a possible cause of AF by initiating fibrosis response and altering electrophysiological properties in atrium. If the hypothesis is confirmed, LPA will act as a new target for AF treatment and administration of LPA receptor blockers may be applied in the prophylaxis of AF.
Assuntos
Fibrilação Atrial/induzido quimicamente , Lisofosfolipídeos/farmacologia , HumanosRESUMO
AIM: To characterize the gene expression profiles in different stages of carcinogenesis of esophageal epithelium. METHODS: A microarray containing 588 cancer related genes was employed to study the gene expression profile at different stages of esophageal squamous cell carcinoma including basal cell hyperplasia, high-grade dysplasia, carcinoma in situ, early and late cancer. Principle component analysis was performed to search the genes which were important in carcinogenesis. RESULTS: More than 100 genes were up or down regulated in esophageal epithelial cells during the stages of basal cell hyperplasia, high-grade dysplasia, carcinoma in situ, early and late cancer. Principle component analysis identified a set of genes which may play important roles in the tumor development. Comparison of expression profiles between these stages showed that some genes, such as P160ROCK, JNK2, were activated and may play an important role in early stages of carcinogenesis. CONCLUSION: These findings provided an esophageal cancer-specific and stage-specific expression profiles, showing that complex alterations of gene expression underlie the development of malignant phenotype of esophageal cancer cells.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica , Neoplasias Esofágicas/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteína Quinase 9 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Distribuição Aleatória , Quinases Associadas a rhoRESUMO
AIM: To study the expression pattern of ETS2 (erythroblastosis virus oncogene homolog 2) in human esophageal squamous cell carcinoma (ESCC). METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and Northern blot were performed to examine the expression level of ETS2 mRNA in 37 pairs of ESCC tissue samples. Western blot and immunohistochemistry were carried out to check the expression level of ETS2 protein in 30 pairs of ESCC tissue specimens. RESULTS: RT-PCR and Northern blot analysis showed that ETS2 mRNA upregulated in 75.7 % (28/37) examined ESCC tissues relative to matched normal tissues. From those 37 cases, 14 cases were randomly selected to perform Western blot and the results revealed that ETS2 protein overexpressed in 71.4 % (10/14) checked ESCC tissues compared with the corresponding normal tissues. Moreover, the expression patterns of ETS2 protein in those 14 cases were identical to those of ETS2 mRNA displayed by RT-PCR or Northern Blot. Immunohistochemistry analysis showed that the expression level of ETS2 protein rose in 75 % (12/16) tumor epithelial cells contrasted to the normal cells. Altogether the expression level of ETS2 protein increased in 73.3 % (22/30) checked ESCC tissue samples contrary to their normal counterparts. CONCLUSION: The results suggested that ETS2 overexpressed in paired human ESCC tissue samples at both mRNA and protein levels and may be associated with the tumorigenesis of esophagus.